Cao Jiahui, Su Ting, Chen Shuilian, Du Zijing, Lai Chunran, Chi Kaiyi, Li Qinyi, Wang Shan, Wu Qiaowei, Hu Yunyan, Fang Ying, Hu Yijun, Zhu Zhuoting, Huang Yu, Zhang Xiayin, Yu Honghua
Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
Br J Ophthalmol. 2025 Jul 22;109(8):868-874. doi: 10.1136/bjo-2024-325771.
Implementing lipid control in patients with diabetes is regarded as a potential strategy for halting the advancement of diabetic retinopathy (DR). This study seeks to use Mendelian randomisation (MR) to assess the causal relationship between lipid traits and lipid-lowering drug targets and full-course DR (background DR, severe non-proliferative DR (NPDR) and proliferative DR (PDR)).
A two-sample MR and drug target MR to decipher the causal effects of lipid traits and lipid-lowering drug targets on full-course DR, including background DR, severe NPDR and PDR, was conducted in the study. Genetic variants associated with lipid traits and genes encoding the protein targets of lipid-lowering drugs were extracted from the Global Lipids Genetics Consortium and UK Biobank. Summary-level data of full-course DR are obtained from FinnGen.
No significant causal relationship was found between lipid traits and full-course DR. However, in drug target MR analysis, peroxisome proliferator-activated receptor gamma (PPARG) enhancement was associated with lower risks of background DR (OR=0.12, p=0.005) and PDR (OR=0.25, p=0.006). Additionally, mediation MR analysis showed that lowering fasting insulin (p=0.015) and HbA1c (p=0.005) levels mediated most of the association between PPARG and full-course DR.
This study reveals PPARG may be a promising drug target for full-course DR. The activation of PPARG could reduce the risk of full-course DR, especially background DR and PDR. The mechanism of the PPARG agonists' protection of full-course DR may be dependent on the glucose-lowering effect.
在糖尿病患者中实施血脂控制被视为阻止糖尿病视网膜病变（DR）进展的一种潜在策略。本研究旨在利用孟德尔随机化（MR）评估血脂性状和降脂药物靶点与全程DR（背景性DR、重度非增殖性DR（NPDR）和增殖性DR（PDR））之间的因果关系。
本研究进行了两样本MR和药物靶点MR，以解读血脂性状和降脂药物靶点对全程DR（包括背景性DR、重度NPDR和PDR）的因果效应。从全球脂质遗传学联盟和英国生物银行中提取与血脂性状相关的基因变异以及编码降脂药物蛋白靶点的基因。全程DR的汇总数据来自芬兰基因库。
未发现血脂性状与全程DR之间存在显著因果关系。然而，在药物靶点MR分析中，过氧化物酶体增殖物激活受体γ（PPARG）增强与背景性DR（OR=0.12，p=0.005）和PDR（OR=0.25，p=0.006）风险降低相关。此外，中介MR分析表明，降低空腹胰岛素（p=0.015）和糖化血红蛋白（HbA1c）水平（p=0.005）介导了PPARG与全程DR之间的大部分关联。
本研究表明PPARG可能是全程DR的一个有前景的药物靶点。PPARG的激活可降低全程DR的风险，尤其是背景性DR和PDR。PPARG激动剂对全程DR的保护机制可能依赖于降糖作用。
